Sandeep Das, Alexandra C. Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H. Pearson-Gallion, M. Peyton McKinney, Koral S. E. Richard, Jose A. Gomez-Vidal, Chowdhury S. Abdullah, Elizabeth D. Cockerham, Joseph Eniafe, Andrew D. Yurochko, Tarek Magdy, Christopher B. Pattillo, Christopher G. Kevil, Babak Razani, Md. Shenuarin Bhuiyan, Erin H. Seeley, Gretchen E. Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T. Garcia-Barrio, Philip L. Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A. Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y. Eugene Chen, Nirav Dhanesha, Paul T. Thevenot, Ari J. Cohen, Arif Yurdagul Jr, Oren Rom
{"title":"抑制肝脏草酸盐过度生成可改善代谢功能障碍相关性脂肪性肝炎","authors":"Sandeep Das, Alexandra C. Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H. Pearson-Gallion, M. Peyton McKinney, Koral S. E. Richard, Jose A. Gomez-Vidal, Chowdhury S. Abdullah, Elizabeth D. Cockerham, Joseph Eniafe, Andrew D. Yurochko, Tarek Magdy, Christopher B. Pattillo, Christopher G. Kevil, Babak Razani, Md. Shenuarin Bhuiyan, Erin H. Seeley, Gretchen E. Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T. Garcia-Barrio, Philip L. Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A. Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y. Eugene Chen, Nirav Dhanesha, Paul T. Thevenot, Ari J. Cohen, Arif Yurdagul Jr, Oren Rom","doi":"10.1038/s42255-024-01134-4","DOIUrl":null,"url":null,"abstract":"The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH. Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 10","pages":"1939-1962"},"PeriodicalIF":18.9000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01134-4.pdf","citationCount":"0","resultStr":"{\"title\":\"Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis\",\"authors\":\"Sandeep Das, Alexandra C. Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H. Pearson-Gallion, M. Peyton McKinney, Koral S. E. Richard, Jose A. Gomez-Vidal, Chowdhury S. Abdullah, Elizabeth D. Cockerham, Joseph Eniafe, Andrew D. Yurochko, Tarek Magdy, Christopher B. Pattillo, Christopher G. Kevil, Babak Razani, Md. Shenuarin Bhuiyan, Erin H. Seeley, Gretchen E. Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T. Garcia-Barrio, Philip L. Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A. Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y. Eugene Chen, Nirav Dhanesha, Paul T. Thevenot, Ari J. Cohen, Arif Yurdagul Jr, Oren Rom\",\"doi\":\"10.1038/s42255-024-01134-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH. 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Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis
The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH. Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.
期刊介绍:
Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.